Synthesis of 1,3-disubstituted bicyclo[1.1.0]butanes via directed bridgehead functionalization†

Abstract

Bicyclo[1.1.0]butanes (BCBs) are increasingly valued as intermediates in ‘strain release’ chemistry for the synthesis of substituted four membered rings and bicyclo[1.1.1]pentanes, with applications including bioconjugation processes. Variation of the BCB bridgehead substituents can be challenging due to the inherent strain of the bicyclic scaffold, often necessitating linear syntheses of specific BCB targets. Here we report the first palladium catalyzed cross-coupling on pre-formed BCBs which enables a ‘late stage’ diversification of the bridgehead position, and the conversion of the resultant products into a range of useful small ring building blocks.

Abstract

Bicyclo[1.1.0]butanes (BCBs) are valuable precursors to four-membered rings and bicyclo[1.1.1]pentanes, and useful bioconjugation agents. We describe a versatile approach to access 1,3-disubstituted BCBs, which are otherwise challenging to prepare.